A number of recent research reports suggest that chromosome translocations in cancer cells disrupt proteins involved in the process of histone acetylation and de-acetylation, and that these abnormal proteins cause aberrant gene repression. Histones are the protein component of chromatin, which comprises DNA supported by histone octamers to form nucleosomes. These histone proteins have lysine rich tails which when deacetylated become charged and attracted to the DNA backbone. This condenses the chromatin structure such that proteins involved in gene transcription cannot gain access, resulting in transcriptional repression.
It has been proposed that inhibition of histone deacetylase (HDAC) enzymes could relieve such gene repression and reinstate the program of differentiation and apoptosis in a manner analogous to the use of retinoic acid in the treatment of acute promyelocytic leukemia—a form of “transcription therapy” A number of compounds that inhibit HDAC have been described, and several are in phase I and II clinical trials. These compounds have been shown to induce cell cycle arrest, differentiation and cell death in cancer cells growing in vitro and in animal xenograft models. The most potent HDAC inhibitor, Trichostatin A (TSA) was isolated from Streptomyces hygroscopicus in the 1970's, as an antifungal antibiotic against trichophyton. Although potent in vitro, TSA has limited stability and is therefore not therapeutically useful. Novel compounds with a similar structure, such as suberoylanilide hydroxamate (SAHA), have activity in pre-clinical models, and have shown some anti-cancer activity in phase I studies. However, this compound is also rapidly eliminated, requiring large doses for activity. Other HDAC inhibitors that have been tested in the phase I setting have major side effects (i.e. Depsipeptide), or affect histone acetylation by an indirect mechanism (CI-994). Others are still undergoing early clinical investigation.
Potent, metabolically stable, HDAC inhibitors would be more therapeutically useful than many of those currently in clinical trials.